Modeling Radiation-induced Cardiovascular Dysfunction with Human iPSC-Derived Engineered Heart Tissues
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE242108 | GEO | 2023/09/05
REPOSITORIES: GEO
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Project description:We sought to determine the long-term effects of radiation (IR) on gene expression in the whole heart as a function of IR type and dose. We hypothesize that compared to low doses of gamma-IR, high charge and energy (HZE) particle-IR may have different biological response thresholds in cardiac tissue at lower doses, and these effects may be IR type- and dose-dependent. We provide for the first time the transcriptome analysis of mouse hearts exposed to low and very low doses of gamma- (137Cs), silicon- (14Si), and titanium- (22Ti) irradiation. Our results show that 16 months after low and very low dose IR exposure, the gene expression in the heart tissue is significantly differentially regulated, suggesting there are long-term effects on dysregulation of varying molecular pathways that are associ-ated with various degrees of cardiovascular, pulmonary and metabolic diseases, as well as biological processes, including abnormal circadian rhythm, cancer, Hutchinson-Gilford progeria syndrome, etc.
2021-01-05 | GSE164234 | GEO
Project description:Rationale Hypertrophic cardiomyopathy (HCM) is the most common cardiac genetic disorder caused by sarcomeric gene variants and is associated with left ventricular hypertrophy and diastolic dysfunction. The role of the microtubule network has recently gained interest with findings that microtubule detyrosination (dTyr-MTs) is markedly elevated in heart failure. Acute reduction of dTyr-MTs by inhibition of the detyrosinase (VASH/SVBP complex) or activation of the tyrosinase (tubulin tyrosine ligase, TTL) markedly improved contractility and reduced stiffness in human failing cardiomyocytes, presenting a new perspective for HCM treatment. Objective In this study, we tested the impact of chronic tubulin tyrosination in a HCM mouse model (Mybpc3-knock-in; KI), in human HCM cardiomyocytes, and in SVBP-deficient human engineered heart tissues (EHTs). Methods and Results AAV9-mediated TTL transfer was applied in neonatal wild-type (WT) rodents, in 3-week-old KI mice, and in HCM human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. We show: i) TTL for 6 weeks dose-dependently reduced dTyr-MTs and improved contractility without affecting cytosolic calcium transients in WT cardiomyocytes. ii) TTL for 12 weeks reduced the abundance of dTyr-MTs in the myocardium, improved diastolic filling, compliance, cardiac output, and stroke volume in KI mice. iii) TTL for 10 days normalized cell area in HCM hiPSC-cardiomyocytes. iv) TTL overexpression activates transcription of several tubulin isoforms, and omics GO analysis revealed enrichment of components of the cytoskeleton, sarcomere Z-disc, mitochondria, and intercalated disc in KI mice. v) SVBP-deficient EHTs exhibited reduced dTyr-MT levels, higher force, and faster relaxation than TTL-deficient and WT EHTs. RNA-seq and mass spectrometry analysis revealed distinct enrichment of cardiomyocyte components and pathways in SVBP-KO vs. TTL-KO EHTs. Conclusion This study provides the first proof-of-concept that chronic activation of tubulin tyrosination in HCM mice and in human EHTs improves heart function and holds promise for targeting the non-sarcomeric cytoskeleton in heart disease.
2024-08-28 | PXD054236 | Pride
Project description:The endothelium is the barrier separating blood and tissue. Radiation-induced enhanced inflammation leading to permeability of this barrier may increase the risk of cardiovascular disease. The aim of this study was to investigate the onset of endothelial inflammatory pathways after radiation exposure. Human coronary artery endothelial cells (HCECest2) were exposed to radiation doses of 0, 0.25, 0.5, 2.0 and 10 Gy (60Co-γ). The cells were harvested 4 h, 24 h, 48 h and 1 wk post-irradiation. The proteomics analysis was performed in a label-free data-independent acquisition mode. The data were validated using bioinformatics and immunoblotting. The low- and moderate-dose-treated samples showed only small proteome changes. In contrast, an activation of DNA-damage repair, inflammation, and oxidative stress pathways was seen after high-dose treatments (2 and 10 Gy). The level of the DNA damage response protein DDB2 was enhanced early at the 10 Gy dose. The expression of proteins belonging to the inflammatory response or cGAS-STING pathway (STING, STAT1, ICAM1, ISG15) increased in a dose-dependent manner showing the strongest effects at 10 Gy after one week. This study suggests a connection between radiation-induced DNA damage and induction of inflammation and supports inhibition of cGAS-STING pathway in the prevention of radiation-induced cardiovascular disease.
2020-11-02 | PXD020735 | Pride
Project description:Background: The effects of dose-rate and its implications on radiation biodosimetry methods are not well studied in the context of large-scale radiological scenarios. There are significant health risks to individuals exposed to an acute dose in such an event, but the most realistic scenario would be a combination of exposure to both high and low dose-rates, from both external and internal radioactivity. It is important therefore, to understand the biological response to prolonged exposure; and further, discover biomarkers that can be used to estimate the extent of damage from low-dose rate exposure and propose appropriate clinical treatment. Methods: We irradiated human whole blood ex vivo to three doses, 0.56 Gy, 2.25 Gy and 4.45 Gy, using two dose rates: 1.1Gy/min and 3.1mGy/min. After 24 hours, we isolated RNA from blood cells and hybridized these to Agilent Whole Human genome microarrays. We validated the microarray results using qRT-PCR. Results: Microarray results showed that there were 454 significantly differentially expressed genes after prolonged exposure to all doses. After acute exposure, 598 genes were differentially expressed to all doses combined. Gene ontology terms enriched in both sets of genes were related to immune processes and B cell mediated immunity. Genes responding to acute exposure was also enriched in functions related to natural killer cell activation and cell-to-cell signaling. As expected, p53 pathway was found to be significantly enriched at all doses and by both dose-rates of radiation. Prediction algorithms were able to distinguish between low dose-rate and acute exposures, on the basis of a group of genes. These maybe candidates for preliminary testing as markers for differences in gene expression based on dose-rate. Radiation induced gene expression was measured in ex vivo irradiated human blood, at the 24hr time point after irradiation. Doses (0.56 Gy, 2.2 Gy and 4.45 Gy) were delivered by two dose rates, acute dose rate of 1Gy/min and low dose rate of 3.1 mGy/min.
2015-04-28 | E-GEOD-65292 | biostudies-arrayexpress
Project description:The biomedical consequences of space radiation pose a significant concern for astronauts engaged in deep space. However, the effects of long-term low dose-rate exposures in space environments remain elusive. In this study, we simulated the space radiation environment by exposing human bronchial epithelial cells to low dose-rate (0.0067 Gy/day) α-particles, and continuously irradiated them multiple times to achieve cumulative total doses of 0.2 Gy, 0.4 Gy, and 0.5 Gy, respectively. At the same time, the cells were irradiated with the same total dose in a single exposure to investigate the potential of low dose-rate alpha particles to induce malignant transformation of human bronchial epithelial cells. A comprehensive suite of assays was employed to assess tumorigenic potential, including tumor formation in NOD/SCID mice, immunohistochemistry, CCK-8 proliferation assay, invasion assay, and the evaluation of multicellular spheroid formation during subsequent passages post-irradiation. Moreover, we dissected differential malignant mechanisms in tumor evolution ecosystem induced by the two distinct irradiation modes from systems biology views based on scRNA-seq technology. Our results showed that exposure to α-particles, whether through a single acute exposure or long-term low dose-rate exposures, induced the occurrence and development of tumors. Long-term low dose-rate exposures to α-particles increase the malignancy of induced tumors, but not the risk of carcinogenesis, compared to a single acute exposure with the same total dose. In addition, through scRNA-seq, we found that long-term low dose-rate exposures triggered more copy number variation (CNV) and epithelial-mesenchymal transition (EMT) events, and the activation of DNA damage repair pathways occurred significantly later than with a single acute exposure and involved more specific changes in cellular communication dynamics. In conclusion, our findings provide emerging yet convincing evidence that not only sheds light on why cells exposed to long-term low dose-rate exposures exhibit heightened malignancy, but also offers valuable insights into the genetic determinants driving tumor evolution and heterogeneity.
2024-08-05 | GSE273937 | GEO
Project description:Background and Purpose: Cardiotoxicity is a well-known adverse effect of radiation therapy. Measurable abnormalities in the heart function indicate advanced and often irreversible heart damage. Therefore, early detection of cardiac toxicity is necessary to delay and alleviate the development of the disease. The present study investigated long-term serum proteome alterations following local heart irradiation using a mouse model with the aim to detect biomarkers of radiation-induced cardiac toxicity. Materials and Methods: Serum samples from C57BL/6J mice were collected 20 weeks after local heart irradiation with 8 Gy or 16 Gy X-ray; the controls were sham-irradiated. The samples were analyzed by quantitative proteomics based on data-independent acquisition mass spectrometry. The proteomics data were further investigated using bioinformatics and ELISA. Results: The analysis showed radiation-induced changes in the level of several serum proteins involved in the acute phase response, inflammation and cholesterol metabolism. We found significantly enhanced expression of pro-inflammatory cytokines (TNF-, TGF-, IL-1 and IL-6) in the serum of the irradiated mice. The level of free fatty acids, total cholesterol, low density lipoprotein (LDL) and oxidized LDL was increased whereas that of high density lipoprotein was decreased by irradiation. Conclusions: This study provides information on systemic effects of heart irradiation. It elucidates a radiation fingerprint in the serum that may be used to elucidate adverse cardiac effects after radiation therapy.
2021-09-10 | PXD024446 | Pride
Project description:Measuring global gene expression using cDNA or oligonucleotide microarrays is an effective approach to understanding the complex mechanisms of the effects of radiation. However, few studies have been carried out that investigate gene expression in vivo after prolonged exposure to low-dose-rate radiation. In this study, C57BL/6J mice were continuously irradiated with γ-rays for 485 days at dose-rates of 0.032 – 13 μGy/min. Gene expression profiles in the kidney and testis from irradiated and unirradiated mice were analyzed, and differentially expressed genes were identified. A combination of pathway analysis and hierarchical clustering of differentially expressed genes revealed that expression of genes involved in mitochondrial oxidative phosphorylation was elevated in the kidney after irradiation at the dose-rates of 0.65 μGy/min and 13 μGy/min. Expression of cell cycle-associated genes was not profoundly modulated in the kidney, in contrast to the response to acute irradiation, suggesting a threshold in the dose-rate for modulation of the expression of cell cycle-related genes in vivo following exposure to radiation. We demonstrated that changes to the gene expression profile in the testis were largely different from those in the kidney. The Gene Ontology categories “DNA metabolism”, “response to DNA damage” and “DNA replication” overlapped significantly with the clusters of genes whose expression decreased with an increase in the dose-rate to the testis. These observations provide a fundamental insight into the organ-specific responses to low-dose-rate radiation. Key Words: kidney, low-dose-rate, radiation, microarray, mitochondrial oxidative phosphorylation, testis
2009-05-27 | GSE14290 | GEO
Project description:Measuring global gene expression using cDNA or oligonucleotide microarrays is an effective approach to understanding the complex mechanisms of the effects of radiation. However, few studies have been carried out that investigate gene expression in vivo after prolonged exposure to low-dose-rate radiation. In this study, C57BL/6J mice were continuously irradiated with ?-rays for 485 days at dose-rates of 0.032 – 13 ?Gy/min. Gene expression profiles in the kidney and testis from irradiated and unirradiated mice were analyzed, and differentially expressed genes were identified. A combination of pathway analysis and hierarchical clustering of differentially expressed genes revealed that expression of genes involved in mitochondrial oxidative phosphorylation was elevated in the kidney after irradiation at the dose-rates of 0.65 ?Gy/min and 13 ?Gy/min. Expression of cell cycle-associated genes was not profoundly modulated in the kidney, in contrast to the response to acute irradiation, suggesting a threshold in the dose-rate for modulation of the expression of cell cycle-related genes in vivo following exposure to radiation. We demonstrated that changes to the gene expression profile in the testis were largely different from those in the kidney. The Gene Ontology categories “DNA metabolism”, “response to DNA damage” and “DNA replication” overlapped significantly with the clusters of genes whose expression decreased with an increase in the dose-rate to the testis. These observations provide a fundamental insight into the organ-specific responses to low-dose-rate radiation. Key Words: kidney, low-dose-rate, radiation, microarray, mitochondrial oxidative phosphorylation, testis 3 biological replicates for each experimental group were analysed. GSE14290_Kidney_raw_data.csv contains the raw data for GSM357146, GSM357425, GSM357426, GSM357452 to GSM357460. GSE14290_Testis_raw_data.csv contains the raw data for GSM357471 to GSM357482. In these files, the sample identifiers are included in the column headers.
2009-05-27 | E-GEOD-14290 | biostudies-arrayexpress
Project description:The heart tissue is a potential target of various noxae contributing to the onset of cardiovascular diseases. However, underlying pathophysiological mechanisms are largely unknown. Human stem cell-derived models are promising, but a major concern is the cell immaturity when estimating risks for adults. In this study, 3D aggregates of human embryonic stem cell-derived cardiomyocytes were cultivated for 300 days and characterized regarding degree of maturity, structure, and cell composition. Furthermore, effects of ionizing radiation (X rays, 0.1–2 Gy) on matured aggregates were investigated, representing one of the noxae that are challenging to assess. Video-based functional analyses were correlated to changes in the proteome after the irradiation. Cardiomyocytes reached maximum maturity after 100 days in cultivation, judged by α-actinin lengths, displayed typical multinucleation and branching. At this time, aggregates contained all major cardiac cell types, proven by the patch-clamp technique. Matured and X-ray-irradiated aggregates revealed a subtle increase in beat rates and decrease in rhythmicity in a dose-dependent manner compared to non irradiated sham controls. The proteome analysis provides first insights into signaling mechanisms contributing to cardiotoxicity. Here, we propose an in vitro model suitable to screen various noxae to target adult cardiotoxicity by preserving all benefits of a 3D tissue culture.
2021-11-04 | PXD028099 | Pride
Project description:Model Context: Model of neural control of cardiovascular behavior and its interaction with respiratory behavior
Primary goal of the model: The primary objective of the modeling study was to evaluate the role of neural signals in controlling the dynamic behavior of the heart, particularly in regulating cardiovascular metrics such as heart rate and blood pressure. We also seek to understand neural control of respiratory sinus arrhythmia, a natural acceleration and deceleration of heart rate in synchronization with respiration, which is characteristic of good cardiovascular health.
Our model builds on a previously developed model of neural control of the heart.1 We extended this model by integrating the “little brain of the heart”, the intrinsic cardiac nervous system (ICN), to study its contributions to cardiovascular control. This newly developed model with the ICN also integrates modeling of the cardiac phase-dependent effect of parasympathetic activity on heart rate deceleration and gating of signals in the brainstem in based on respiratory phase to represent a possible mechanism of respiratory sinus arrhythmia (RSA). Our expanded model can be utilized to explore the role of the ICN on beat-to-beat cardiovascular behavior, specifically RSA. Simulations can be performed to explore regulation of cardiovascular behavior in response to changes in lung tidal volume and electrical stimulation of the vagus nerve, which connects the brain and the heart.
2024-02-27 | MODEL2402270001 | BioModels